MicroRNAs (miRNAs) represent a novel class of ubiquitous and highly abundant gene regulatory elements with important roles in the control of gene expression in plants and animals. Like transcription factors, miRNAs have the potential to regulate thousands of genes, and, indeed, predictions suggest that a significant percentage of the human genome is targeted by miRNAs. Consistent with this, miRNAs have been implicated in an impressive array of functions, including development, cancer, and immunity. Yet, the function of the vast majority of miRNAs remains uncharacterized. We have previously identified multiple miRNAs that are differentially expressed during aging and discovered important roles for several of these in longevity, caloric restriction and stress resistance. The overall goal of te current proposal is to delineate the genetic networks that link stress response to miRNAs and associate these with biomedically relevant genetic pathways. To that end, this proposal aims to utilize the model organism C. elegans to: 1) Identify the miRNA target genes and pathways regulated by aging-associated miRNAs using a combination of transcriptome surveying and functional genetics; 2) Identify upstream genetic regulators of stress-associated miRNAs by testing, via expression studies and functional genetics, the role of specific transcription factors as candidate upstream regulators of aging-associated miRNAs; and 3) Determine the functions of miRNAs in models of neurodegeneration and proteotoxic stress. The model organism C. elegans is ideally suited for an undergraduate research setting and it is the model of choice for the research aims delineated in this project. Given the high conservation of miRNAs and their targets across strata we expect that discoveries made in C. elegans about the genetic networks that underlie miRNA function in stress resistance will be applicable to diseases of biomedical importance in humans.